Ingenol Mebutate Treatment in Actinic Keratosis – Clinical Effectiveness and Potential Side Effects

Original paper

Ingenol mebutate treatment in actinic keratosis – clinical effectiveness and potential side effects

Aleksandra Lesiak1, Anna Maćkowska2, Igor A. Bednarski1, Paweł Kolano3, Irmina Olejniczak-Staruch4, Anna Woźniacka4, Joanna Sieniawska4, Joanna Narbutt1

1Department of Dermatology, Pediatric Dermatology and Oncology, Medical University of Lodz, Lodz, Poland 2Student Research Group at Department of Dermatology, Pediatric Dermatology and Oncology, Medical University of Lodz, Lodz, Poland 3Department of General and Oncological Surgery, Tomaszow Health Centre, Tomaszow Mazowiecki, Poland 4Department of Dermatology and Venereology, Medical University of Lodz, Lodz, Poland Adv Dermatol Allergol 2019; XXXVI (4): 468–471 DOI: https://doi.org/10.5114/ada.2019.87450

Abstract Introduction: Actinic keratosis is a common skin disease that occurs in response to prolonged exposure to ultraviolet radiation. This problem affects up to 60% of the population over 40 years of age. Actinic keratosis is considered to be a precancerous lesion leading to squamous cell carcinoma (SCC). The new therapeutic option for the treatment of actinic keratosis is ingenol mebutate gel (0.015%, 0.05%). Aim: Retrospective evaluation of response and potential side effects of ingenol mebutate treatment in clinical practice. Material and methods: Eight patients with actinic keratosis lesions on the face or scalp self-applied a 0.015% gel for 3 consecutive days on the 25 cm2 marked area. They were assessed at baseline and on day 4, 7, 14 and 57. Results: All patients on day 57 presented a complete absence of AK lesions in the area of ingenol mebutate application. No adverse events were observed. Conclusions: Our study shows that ingenol mebutate is highly efficacious field treatment for actinic keratosis. Key words: actinic keratosis, ingenol mebutate.

Introduction changes, which is why the overall risk of squamous cell Actinic keratosis (AK) is a common skin disease that carcinoma is cumulative. It is estimated that a patient occurs in response to excessive exposure to ultraviolet with 7–8 lesions of AK has a 6.1–10.2% risk of developing (UV) radiation. This disease affects up to 60% of general SCC within 10 years. In addition, 60–82% of SCCs are pro- population over 40 years of age, that is highly exposed to duced directly at or near the AK changes [4]. ultraviolet radiation [1]. Prevalence is dependent on many Unfortunately, it is not possible to assess which AK factors such as age, gender, latitude, fair skin (Fitzpatrick plaques will transform into SCC, thus it is important to skin types I–III), but also immunodeficiencies or human treat AK lesions effectively. papillomavirus infections [2]. Treatment regimens in AK could be divided into le- Actinic keratosis is a disease characterized by the sion-directed and field-directed therapies. Selecting presence of hyperkeratotic, scaly papules or plaques, lim- a therapy for a particular patient must always be sup- ited to the epidermis. Changes occur more often in places ported by a history of disease, the amount and localiza- exposed to the ultraviolet radiation than other, e.g. the tion of lesions, the overall level of sun damage, and the face, scalp and forearms. Actinic keratosis is considered patient’s ability to cooperate and willingness to follow to be a precancerous lesion that, in some cases, might medical advice. Lesion-directed therapy consists of cryo- lead to squamous cell carcinoma (SCC) [3]. Although the therapy, curettage with electrostimulation and chemical probability of a tumor transformation of singular lesions peels. Cryosurgery with liquid nitrogen is one of the most is quite low, it should be noted that patients who were commonly used methods in the US [5] and is dedicated highly exposed to the ultraviolet radiation have many AK to people with many, not very large and well-demarcated

Address for correspondence: Igor A. Bednarski MD, Department of Dermatology, Pediatric Dermatology and Oncology, Medical University of Lodz, 1/5 Kniaziewicza St, 91-347 Lodz, Poland, phone: + 48 666 379 108, e-mail: [email protected] Received: 5.03.2018, accepted: 11.05.2018.

468 Advances in Dermatology and Allergology 4, August / 2019

Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-27 Ingenol mebutate treatment in actinic keratosis – clinical effectiveness and potential side effects

changes. Unfortunately, the common side effect of this Material and methods therapy is hypopigmentation of the skin as well as pain ten patients of the Department of Dermatology and during the treatment. In addition, changes tend to re- Venereology of the Medical University of Lodz were qual- cur [6]. The field-directed therapy is targeted at people ified for ingenol mebutate treatment. All patients pre- with multiple lesions located in similar localizations and sented Fitzpatrick phototype I, II or III and had changes with a subclinical AK. This approach includes methods of actinic keratosis within the scalp (scalp or forehead). such as dermabrasion, photodynamic and laser therapy, Patients were aged between 68 and 84 years. The study as well as topical agents: 5-fluorouracil, imiquimod, 3% involved 9 men and 1 woman. Each patient presented diclofenac gel. A large limitation of topical application is an area of 25 cm2 occupied by AK changes. Patients with their recommended time of use. Imiquimod, depending hypertrophic lesions, who recently used immunosuppres- on the formulation, must be used for weeks/months, sive or immunomodulatory medications, were excluded. fluorouracil for weeks, and diclofenac for months [7]. In Patients had been self-applying a 0.015% gel on the addition, according to the literature, 5-fluorouracil and marked area for 3 consecutive days. Each of them was imiquimod cause skin irritation that leads to a serious assessed at baseline and on day 4, 7, 14 and 57. discomfort, intolerable to a number of patients. It results The effects of treatment are shown in Figure 1. in discontinuation of the treatment. On the other hand, On day 57, all patients presented a complete absence diclofenac can cause allergic reactions [8]. of AK lesions in the area of ingenol mebutate application. The best results in treating AK lesions have been In every treated patient there were observable local skin achieved by combining lesion-directed and field-direct- reactions that could be classified as erythema, flaking, ed techniques. It is reported that combining diclofenac crusting and swelling, of various intensity. The presence [9] with imiquimod [10] or 5-fluorouracil [11], before cryo- and intensification of those local reactions peaked on therapy, is successful. day 4. Two patients presented a severe local skin reaction The new therapeutic option for the treatment of ac- with a bacterial superinfection. They received antibiotics: tinic keratosis is ingenol mebutate gel (0.015%, 0.05%). doxycycline (200 mg in two doses for 10 days) and fusidic A 0.015% gel is intended for daily use on the face or scalp acid (applied on the skin twice a day for 10 days). Four for 3 consecutive days, while a 0.05% gel is dedicated to patients had moderate and other 4 mild local skin reac- patients with AK lesions in the extremities and trunk and tions. However, those symptoms were temporary and not should be applied once a day for 2 consecutive days. In troublesome for the patients. our article we would like to present results of the treatment of 10 patients in the Department of Dermatology Discussion and Venereology of the Medical University of Lodz. Ingenol mebutate is a diterpene ester, which is ex- tracted from the plant called Euphorbia peplus. In the Aim past, the sap of the plant was used as a remedy for many Retrospective evaluation of response and potential skin diseases [12]. side effects of ingenol mebutate treatment in the clinical Ingenol mebutate has multiple mechanisms of ac- practice among Polish patients. tion. One of them is an initial chemoablation by disrup-

Day 0 (predose) Day 4 Day 7 Day 14 Day 57

Figure 1. Effect of treatment in 3 selected patients from baseline (day 0) to day 57

Advances in Dermatology and Allergology 4, August / 2019 469

Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-27 A. Lesiak, A. Maćkowska, I.A. Bednarski, P. Kolano, I. Olejniczak-Staruch, A. Woźniacka, J. Sieniawska, J. Narbutt

tion of the plasma membrane and mitochondria, which ingenol mebutate treatment compared to UVR alone leads to a loss of mitochondrial membrane potential (UVR 10.25 vs. UVR + ingenol mebutate 6.0; p = 0.002). and, ultimately, necrosis of locally affected cells. The A topical usage of clobetasol propionate to reduce local second mechanism of action is elimination of tumor skin reactions was also assessed. Surprisingly, clobetasol cells by the tumor-specific antibodies, which proinflam- propionate increased LSR (max LSR Tx 1-5: UVR + inge- matory cytokines and massive releasing of neutrophils nol mebutate + Clobetasol propionate 3.6–5.5 vs. UVR + – leading to neutrophil-and antibody dependent cellular ingenol mebutate 2.6–4.3) but at the same time provided cytotoxicity [13, 14]. better prevention of the photodamage [20]. Lebwohl et al. [7] in two of their studies confirmed The treatment with the ingenol mebutate gel could a high efficacy of ingenol mebutate. Studies (n = 547) also be beneficial from a social point of view. In Greece, examined the ingenol mebutate 0.015% gel versus a ve- ingenol mebutate 0.05% and 0.015% were the most hicle for 3 days in AK on the face or scalp while other cost-effective topical treatment options, compared to di- studies (n = 458) tested ingenol mebutate 0.05% versus clofenac and imiquimod (incremental cost-effectiveness a vehicle for 2 days in AK on the trunk or extremities. ratio of € 30,000 and € 10,868 per quality adjusted life- Patients had been applying the substance on AK areas of year QALY, respectively) [21]. 25 cm2. The median reduction in the lesion count was 83% with 0.015% gel and 75% with 0.05% gel, compared to a 0% reduction in both groups using the vehicle. Conclusions Among patients using ingenol mebutate on the scalp, To sum up, in our study, the 0.015% ingenol mebutate the most common skin reaction was pain (13.9%), pruri- gel applied to the face or scalp once a day on 3 consecu- tus (8%) and irritation (1.8%). No serious adverse events tive days was effective in treating actinic keratosis. were observed [7]. Moreover, Jim On et al. [15] analyzed The big advantage of using ingenol mebutate is that a relation between AK lesions count at week 8 adjusted we can achieve a big efficacy after only 2 or 3 applica- for baseline and composite LSR score (local skin reaction tions. Many patients have problems with regular use score). The percentage reduction in AK lesions was higher which can lower effectiveness reported beforehand in in patients with a higher LSR score. A large skin reaction clinical trials. A short-time treatment (like 2–3 applica- after ingenol mebutate treatment gives more reliable tions) increases the probability of the patient compliance. probability of AK clearance [15]. Another benefit of a short-time usage is that local reac- The same clearance rate as after using ingenol me- tions disappear relatively quickly. On the face or scalp the butate for 2–3 days is achieved with other field thera- peak of the local skin response was observed on day 4 pies but it requires a longer treatment period. Using but already on day 15, almost all of it has been resolved. 5-fluorouracil in a 4-week treatment leads to a complete Our study and all reviewed studies show that ingenol clearance rate of 43% [16]. A treatment with imiquimod mebutate is highly efficacious and has a generally tem- causes complete clearance rates from 25% to 35.5% after porary and mild to moderate local skin response. Even in 2 or 3 weeks’ treatment [17]. cases where severe skin reactions appear, the final cos- In another trial, patients received ingenol mebutate on metic effect is very good and satisfying to our patients. 2 approximately 250 cm sun-damaged skin for three con- These findings suggest that ingenol mebutate could be secutive days. Of 61 patients, 10 had a subnanomolar lev- a first-line field treatment for actinic keratosis. el of ingenol mebutate in whole blood (0.235–0.462 nM). No serious adverse reactions were observed, most of them were mild to moderate in intensity [18]. Acknowledgments Ingenol mebutate could also be a concurrent treat- The study was funded by Medical University of Lodz, ment used in order to increase the effectiveness of the project no. 503/5-064-01/503-01 and 503/1-152-01/503-01. therapy. Hashim et al. confirm that application of the 0.05% ingenol mebutate gel on the same day as a cryosurgery is more effective in reducing numerous hyperker- Conflict of interest atotic actinic keratosis lesions (–4.3 vs. –2.8 in the control The authors declare no conflict of interest. group) and non-hyperkeratotic lesions (–3.8 vs. –0.8 in the control group). No significant increase in the number References of local skin reactions was observed [19]. Erlendsson et al. demonstrated in a trial with hair- 1. Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines of care less mice that ingenol mebutate prevents progression for actinic keratoses. Committee on Guidelines of Care. J Am Acad Dermatol 1995; 32: 95-8. of UV-induced photodamages. Sixty hairless mice were 2. Bouwes Bavinck JN, Euvrard S, Naldi L, et al. EPI-HPV-UV- exposed to the ultraviolet radiation and received five sin- CA group. Keratotic skin lesions and other risk factors are gle treatments at 4 weeks’ intervals. On day 140, a stan- associated with skin cancer in organ-transplant recipients: dardized UV-damage scale (0–12) was lower in mice with a case-control study in the Netherlands, United Kingdom,

470 Advances in Dermatology and Allergology 4, August / 2019

Germany, France, and Italy. J Invest Dermatol 2007; 127: 18. Bucko AD, Jarratt M, Stough DB, et al. Pharmacokinetics of 1647-56. ingenol mebutate gel under maximum use conditions in 3. de Berker D, McGregor JM, Hughes BR. British Association large treatment areas. J Dermatolog Treat 2017; 29: 74-9. of Dermatologists Therapy Guidelines and Audit Subcom- 19. Hashim PW, Nia JK, Singer S, Goldenberg G. An investigator- mittee, Guidelines for the management of actinic keratoses. initiated study to assess the safety and efficacy of ingenol Br J Dermatol 2007; 156: 222-30. mebutate 0.05% gel when used after cryosurgery in the 4. Smith ES, Feldman SR, Fleischer AB, et al. Characteristics treatment of hypertrophic actinic keratosis on dorsal hands. of office-based visits for skin cancer. Dermatologists have J Clin Anesthet Dermatol 2016; 9: 16-22. more experience than other physicians in managing malig- 20. Erlendsson AM, Thaysen-Petersen D, Bay C, et al. Repeated nant and premalignant skin conditions. Dermatol Surg 1998; treatments with ingenol mebutate prevents progression of 24: 981-5. uv-induced photodamage in hairless mice. PLoS One 2016; 5. Halpern AC, Hanson LJ. Awareness of, knowledge of and 11: e0162597. attitudes to nonmelanoma skin cancer (NMSC) and actinic 21. Athanasakis K, Boubouchairopoulou N, Tarantilis F, et al. keratosis (AK) among physicians. Int J Dermatol 2004; 43: Cost-effectiveness of ingenol mebutate gel for the treatment 638-42. of actinic keratosis in Greece. Clin Ther 2017; 39: 993-1002. 6. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A ran- domised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007; 157 Suppl 2: 34-40. 7. Lebwohl M, Swanson N, Anderson LL, et al. Berman, Ingenol mebutate gel for actinic keratosis. N Engl J Med 2012; 366: 1010-9. 8. Spencer JM, Hazan C, Hsiung SH, Robins P. Therapeutic de- cision making in the therapy of actinic keratoses. J Drugs Dermatol 2005; 4: 296-301. 9. Berlin JM, Rigel DS. Diclofenac sodium 3% gel in the treatment of actinic keratoses postcryosurgery. J Drugs Dermatol 2008; 7: 669-73. 10. Jorizzo J, Weiss J, Vamvakias G. One-week treatment with 0.5% fluorouracil cream prior to cryosurgery in patients with actinic keratoses: a double-blind, vehicle-controlled, long- term study. J Drugs Dermatol 2006; 5: 133-9. 11. Jorizzo JL, Markowitz O, Lebwohl MG, et al. A randomized, double-blinded, placebo-controlled, multicenter, efficacy and safety study of 3.75% imiquimod cream following cryosurgery for the treatment of actinic keratoses. J Drugs Dermatol 2010; 9: 1101-8. 12. Green AC, Beardmore GL. Home treatment of skin cancer and solar keratoses. Australas J Dermatol 1988; 29: 127-30. 13. Ogbourne SM, Suhrbier A, Jones B, et al. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res 2004; 64: 2833-9. 14. Challacombe JM, Suhrbier A, Parsons PG, et al. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J Immunol 2006; 177: 8123-32. 15. Jim On S, Knudsen KM, Skov T, Lebwohl M, Regression analy- sis of local skin reactions to predict clearance of actinic keratosis on the face in patients treated with ingenol mebutate gel: experience from randomized controlled trials. J Drugs Dermatol 2017; 16: 112-4. 16. Loven K, Stein L, Furst K, Levy S. Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther 2002; 24: 990-1000. 17. Swanson N, Abramovits W, Berman B, et al. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol 2010; 62: 582-90.

Advances in Dermatology and Allergology 4, August / 2019 471

Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-09-27